Genetic Causes of HypophosphatemiaIn 2006, we identified the genetic defect underlying the childhood disorder hereditary hypophosphatemic rickets with hypercalciuria (HHRH). HHRH is caused by mutations in NaPi-IIc, a renal sodium-phosphate co-transporter, which is important to conserving phosphate in the kidney and leads to hypophosphatemia and rickets when lost. Our research goal is now to study the role of NaPi-IIc in human phosphate homeostasis and to understand the phenotypic variability of patients suffering from HHRH. For this purpose, we are currently using mammalian and Xenopus oocyte expression systems to study the functional properties of the identified human NaPi-IIc mutations in vitro. Plans for the near future are to establish mouse models to study the role of NaPi-IIc and some of the human mutations in vivo.

We also established international collaborations to look for NaPi-IIc mutations in new patients suffering from HHRH both to establish their molecular diagnosis and to carefully study their symptoms to see whether only some or all patients are at risk for developing kidney stones.

Metabolic and homeostatic effects of phosphateA more recent research interest is in trying to understand how human and other metazoan cells sense inorganic phosphate to explain the effects of phosphate on:

Cell metabolism (metabolic sensing)

How phosphate feeds back to regulate the above hormonal systems (homeostatic sensing)

Whether metabolic and homeostatic sensors use the same signal transduction cascades

For this purpose, we have performed a genome-wide Drosophila RNAi knockdown using phosphate-induced activation of MAPK (in vitro) in collaboration with Stephanie Mohr, Elizabeth Perkins and Norbert Perrimon of Harvard Medical School. We identified 103 genes, including 85 phosphate-specific genes and evaluated the genes in live flies with assays for dietary phosphate toxicity, hemolymph phosphate and life span. Our goal in the next five years will be to identify mammalian systems suitable to study phosphate sensing. The team will also continue exploring Drosophila melanogaster as a model organism. Relevant readouts for humans will be the homeostatic regulation of the synthesis and secretion of PTH, 1,25-D and FGF23 by phosphate and its metabolic effect on life-span in genetic disorders, such as familial hyperphosphatemic tumoral calcinosis (FHTC) and chronic kidney disease.

Clinical WorkI attend on the endocrine consult service at Massachusetts General Hospital and see outpatients with a focus on disorders of minerals and metabolism as a member of the Mass General Endocrine Associates. Furthermore, I also participate as faculty in the annual endocrine postgraduate course in Boston.

Past and Current Funding:

Young investigator awards by the National Kidney Foundation (2006-2008) and the American Society of Clinical Investigation (2007)